Benzodiazepine derivatives, compositions, and methods for treating cognitive impairment
This invention relates to benzodiazepine derivatives, compositions comprising therapeutically effective amounts of those benzodiazepine derivatives and methods of using those derivatives or compositions in treating cognitive impairment associated with central nervous system (CNS) disorders. In particular, it relates to the use of a α5-containing GABA A receptor agonist (e.g., a α5-containing GABA A receptor positive allosteric modulator) as described herein in treating cognitive impairment associated with central nervous system (CNS) disorders in a subject in need or at risk thereof, including, without limitation, subjects having or at risk for age-related cognitive impairment, Mild Cognitive Impairment (MCI), amnestic MCI (aMCI), Age-Associated Memory Impairment (AAMI), Age Related Cognitive Decline (ARCD), dementia, Alzheimer's Disease (AD), prodromal AD, post traumatic stress disorder (PTSD), schizophrenia, bipolar disorder, amyotrophic lateral sclerosis (ALS), cancer-therapy-related cognitive impairment, mental retardation, Parkinson's disease (PD), autism spectrum disorders, fragile X disorder, Rett syndrome, compulsive behavior, and substance addiction.
1. A compound of formula II:
or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , and —OCF 3 , wherein each of said (C1-C6)alkyl is independently substituted with 0-5 R′;
R 2 is selected from: —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)-aryl-O—(C1-C12)aliphatic-, (C6-C10)-aryl-(C1-C12)aliphatic-O—, (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-, (5- to 10-membered heteroaryl)-O—(C1-C12)-aliphatic-, and (5- to 10-membered heteroaryl)-(C1-C12)-aliphatic-O—, wherein each of said aliphatic, alkyl, aryl or heteroaryl is independently substituted with 0-5 R′;
R 3 is selected from: —(C1-C6)alkyl, —SO 2 ((C1-C6)alkyl), —C(O)N((C1-C6)alkyl) 2 , and —C(O)O((C1-C6)alkyl), wherein each of said (C1-C6)alkyl is independently substituted with 0-5 R′;
R 4 and R 5 are each independently selected from —H, halogen and —(C1-C6)alkyl; and
R 6 is selected from —H and —(C1-C6)alkyl;
wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″ 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ; and
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-.
2. The compound according to claim 1 , wherein:
m is 0, 1 or 2;
when m is 1 or 2, at least one occurrence of R 1 is halogen or —O((C1-C6)alkyl);
R 2 is selected from: —(C1-C6)alkyl, (C6-C10)-aryl-(C1-C12)aliphatic-, and (C6-C10)-aryl-O—(C1-C12)aliphatic-, wherein each of said alkyl, aryl, or aliphatic is independently substituted with 0-5 R′ independently selected from —F, -Me, and —OMe;
R 3 is —C(O)O((C1-C6)alkyl);
R 4 and R 5 are both —H; and
R 6 is —H.
3. A compound of formula II:
or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, wherein:
m is 0-3;
each R 1 is independently selected from: halogen, —H, —(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —NO 2 , —CN, —CF 3 , and —OCF 3 , wherein each of said —(C1-C6)alkyl or —O((C1-C6)alkyl is independently substituted with 0-5 R′;
R 2 is selected from:
—(C1-C6)alkyl, —OH, —O((C1-C6)alkyl), —C(O)O((C1-C6)alkyl),
(C6-C10)-aryl-(C1-C12)aliphatic-,
(C6-C10)-aryl-O—(C1-C12)aliphatic-,
(C6-C10)-aryl-N(R″)—(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-O—(C1-C12)aliphatic-,
(5- to 10-membered heteroaryl)-N(R″)—(C1-C12)aliphatic-,
(3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-,
(3- to 10-membered heterocyclyl)-O—(C1-C12)aliphatic-, and
(3- to 10-membered heterocyclyl)-N(R″)—(C1-C12)aliphatic-,
wherein R 2 , with the exception of —OH, is independently substituted with 0-5 R′;
R 3 is selected from:
—(C1-C6)alkyl, —C≡CH, —CN, halogen, —SO 2 ((C6-C10)-aryl), —SO 2 ((C1-C6)alkyl), —C(O)N((C1-C6)alkyl) 2 , —C(O)NH 2 , —C(O)O((C1-C6)alkyl), —C(O)((C1-C6)alkyl), —(C6-C10)aryl, and 5- to 10-membered heteroaryl, wherein R 3 with the exception of halogen and —CN is independently substituted with 0-5 R′;
R 4 and R 5 are each independently selected from —H, halogen and -(C1-C6)alkyl; and
R 6 is selected from —H and -(C1-C6)alkyl;
wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″ 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ; and
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-.
4. The compound according to claim 3 , wherein:
m is 0, 1 or 2;
when m is 1 or 2, at least one occurrence of R 1 is halogen or —O((C1-C6)alkyl);
R 2 is selected from:
—(C1-C6)alkyl, (C6-C10)-aryl-(C1-C12)aliphatic-, (C6-C10)aryl-O—(C1-C12)aliphatic-, (5- to 10-membered heteroaryl)-(C1-C12)aliphatic-, and (3- to 10-membered heterocyclyl)-(C1-C12)aliphatic-, wherein R 2 is independently substituted with 0-3 R′;
R 3 is halogen, —CN, —C≡CH, —C(O)NH 2 , —(C1-C6)alkyl, —C(O)((C1-C6)alkyl), —C(O)O((C1-C6)alkyl), —SO 2 (Ph(Me)),
wherein R 9 is selected from —H, -Me, -Et, —CF 3 , isopropyl, —OMe, -tert-butyl and cyclopropyl; and
wherein R 3 with the exception of halogen and —CN is independently substituted with 0-3 R′,
R 4 and R 5 are both —H;
R 6 is —H;
wherein each occurrence of R′ is independently selected from halogen, —R″, —OR″, oxo, —CH 2 OR″, —CH 2 NR″ 2 , —C(O)N(R″) 2 , —C(O)OR″, —NO 2 , —NCS, —CN, —CF 3 , —OCF 3 and —N(R″) 2 ; and
wherein each occurrence of R″ is independently selected from H, —(C1-C6)-alkyl, (C3-C6)-cycloalkyl, 3- to 6-membered heterocyclyl, 5- to 10-membered heteroaryl-, (C6-C10)-aryl-, (5- to 10-membered heteroaryl)-(C1-C6)-alkyl-, (C6-C10)-aryl-(C1-C6)-alkyl-, (5- to 10-membered heteroaryl)-O—(C1-C6)-alkyl-, and (C6-C10)-aryl-O—(C1-C6)-alkyl-.
5. The compound according to claim 4 , wherein R 3 is:
wherein R 9 is selected from —H, -Me, -Et, —CF 3 , isopropyl, —OMe, and -tert-butyl.
6. A compound selected from:
Compound
Structure
1
2
3
4
5
6
9
10
11
12
44
45
46
47
48
49
50
51
52
53
54
101
102
107
108
109
110
111
112
113
114
115
116
117
121
125
126
127
132
133
134
135
136
139
140
143
144
145
146
149
150
151
152
153
154
155
160
161
167
168
170
or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof.
7. A pharmaceutical composition comprising a compound according to claim 1 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, in a therapeutically effective amount; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
8. The pharmaceutical composition according to claim 7 , wherein said composition further comprises
(a) an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof,
(b) memantine, or
(c) an acetylcholine esterase inhibitor (AChE-I) selected from donepezil, galantamine, and rivastigmine, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
9. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 7 .
10. The method of claim 9 , wherein the CNS disorder is age-related cognitive impairment.
11. The method of claim 10 , wherein the age-related cognitive impairment is Mild Cognitive Impairment (MCI).
12. The method of claim 11 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (AMCI).
13. The method according to claim 9 , wherein the CNS disorder is dementia.
14. The method of claim 13 , wherein the dementia is Alzheimer's disease.
15. The method of claim 9 , wherein the CNS disorder is schizophrenia or bipolar disorder.
16. The method of claim 9 , wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).
17. The method of claim 9 , wherein the CNS disorder is post traumatic stress disorder (PTSD).
18. The method of claim 9 , wherein the CNS disorder is associated with cancer therapy.
19. The method of claim 9 , wherein the CNS disorder is mental retardation.
20. The method of claim 9 , wherein the CNS disorder is Parkinson's disease (PD).
21. The method of claim 9 , wherein the CNS disorder is autism.
22. The method of claim 9 , wherein the CNS disorder is compulsive behavior.
23. The method of claim 9 , wherein the CNS disorder is substance addiction.
24. A pharmaceutical composition comprising a compound according to claim 3 , or a pharmaceutically acceptable salt, hydrate, isomer, or combination thereof, in a therapeutically effective amount; and a pharmaceutically acceptable carrier, adjuvant or vehicle.
25. The pharmaceutical composition according to claim 24 , wherein said composition further comprises
(a) an antipsychotic selected from aripiprazole, olanzapine and ziprasidone, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof,
(b) memantine, or
(c) an acetylcholine esterase inhibitor (AChE-I) selected from donepezil, galantamine, and rivastigmine, and the pharmaceutically acceptable salts, hydrates, solvates, and polymorphs thereof.
26. A method of treating cognitive impairment associated with a central nervous system (CNS) disorder in a subject in need thereof, comprising the step of administering a pharmaceutical composition according to claim 24 .
27. The method of claim 26 , wherein the CNS disorder is age-related cognitive impairment.
28. The method of claim 27 , wherein the age-related cognitive impairment is Mild Cognitive Impairment (MCI).
29. The method of claim 28 , wherein the Mild Cognitive Impairment is amnestic Mild Cognitive Impairment (AMCI).
30. The method according to claim 26 , wherein the CNS disorder is dementia.
31. The method of claim 30 , wherein the dementia is Alzheimer's disease.
32. The method of claim 26 , wherein the CNS disorder is schizophrenia or bipolar disorder.
33. The method of claim 26 , wherein the CNS disorder is amyotrophic lateral sclerosis (ALS).
34. The method of claim 26 , wherein the CNS disorder is post traumatic stress disorder (PTSD).
35. The method of claim 26 , wherein the CNS disorder is associated with cancer therapy.
36. The method of claim 26 , wherein the CNS disorder is mental retardation.
37. The method of claim 26 , wherein the CNS disorder is Parkinson's disease (PD).
38. The method of claim 26 , wherein the CNS disorder is autism.
39. The method of claim 26 , wherein the CNS disorder is compulsive behavior.
40. The method of claim 26 , wherein the CNS disorder is substance addiction.